Adiponectin is a protein that is specifically produced and secreted from adipocytes, and is intimately involved in energy balance and glucose or lipid metabolism (Maeda, K. et al., Biochemical and Biophysical Research Communications, 1996, 221, 286-289). In actuality, in patients with circulatory diseases, diabetes, obesity, etc., blood adiponectin concentration decreases (Ouchi, N. et al., Circulation, 1999, 100, 2473-2476; Lindsay, R. S. et al., Lancet, 2002, 360, 57-58; Arita, Y. et al., Biochemical and Biophysical Research Communications, 1999, 257, 79-83). In addition, kidney disease patients exhibiting low blood adiponectin concentrations are known to have a higher mortality rate due to circulatory diseases than patients with high blood adiponectin concentrations (Zoccali, C. et al., Journal of American Society of Nephrology, 2002, 13, 134-141). Thus, disease states having decreased blood adiponectin concentrations, namely hypoadiponectinemia, are thought to be intimately related to lifestyle diseases such as circulatory diseases (arteriosclerosis, hypertension, etc.), diabetes or obesity, and are believed to be one of their basic causes (Weyer, C. et al., The Journal of Clinical Endocrinology & Metabolism, 2001, 86, 1930-1935; Hotta, K. et al., Diabetes, 2001, 50, 1126-1133). Thus, the treatment or prevention of hypoadiponectinemia is also useful in the treatment or prevention of the aforementioned lifestyle diseases caused by hypoadiponectinemia.
Adiponectin is known to have actions of suppressing adhesion of THP-1 cells to vascular endothelial cells, expression of adhesion molecules, differentiation of vascular smooth muscle cells, macrophage foam cell formation, and the like (Ouchi, N. et al., Circulation, 1999, 100, 2473-2476; Ouchi, N. et al., Circulation 2001, 103, 1057-1063; Arita, Y. et al., Circulation 2002, 105, 2893-2898; Ouchi, N. et al., Circulation, 2000, 102, 1296-1301; Yokota, T. et al., Blood, 2000, 96, 1723-1732). These biological phenomena are intrinsic phenomena that occur during the initial stage of the onset of arteriosclerosis (Ross, R. et al., Nature, 1993, 362, 801-809), and the inhibitory effects demonstrated by adiponectin on these phenomena are extremely useful for the treatment or prevention of arteriosclerosis. In addition, increasing adiponectin concentration has been shown to have therapeutic effects on arteriosclerosis in an actual animal model (Okamoto, Y. et al., Circulation, 2002, 106, 2767-2770).
In addition, adiponectin is also intimately related to insulin resistance and diabetes (Kondo, H. et al., Diabetes, 2002, 51, 2325-2328). Insulin resistance is known to increase in the presence of hypoadiponectinemia (Weyer, C. et al., The Journal of Clinical Endocrinology & Metabolism, 2001, 86, 1930-1935; Hotta, K. et al., Diabetes, 2001, 50, 1126-1133), and in an animal model, administration of adiponectin is known to demonstrate glucose metabolism ameliorative action by having effects of improving insulin resistance, suppressing glucose production in the liver, and the like (Yamauchi, T., et al., Nature Medicine, 2001, 7, 941-946; Berg, A. H. et al., Nature Medicine, 2001, 7, 947-953; Combs, T. P. et al., Clinical Investigation, 2001, 108, 1875-1881). Thus, increasing blood adiponectin concentration is useful for the treatment or prevention of diabetes and diabetes complications caused thereby.
Diseases states that exhibit increased insulin resistance, namely insulin resistance syndrome, are considered to be a principal cause of diabetes as well as the fundamental cause of lifestyle diseases such as circulatory diseases (arteriosclerosis, hypertension, etc.) or obesity (McVeigh, G. E. et al., Current Diabetes Reports, 2003, 3, 87-92; Chaudhuri, A. et al., Current Diabetes Reports, 2002, 2, 305-310; Sorisky, A. et al., American Journal of Therapeutics, 2002, 9, 516-521), and improvement of insulin resistance plays an important role in the treatment or prevention of the aforementioned lifestyle diseases. In other words, improvement of insulin resistance is also useful for the treatment or prevention of the aforementioned lifestyle diseases caused by insulin resistance syndrome. As previously mentioned, since adiponectin has an action of improving insulin resistance (Yamauchi, T. et al., Nature Medicine, 2001, 7, 941-946), a medicament that enhances adiponectin production is useful for the treatment or prevention of insulin resistance syndrome, as well as the treatment or prevention of diabetes, diabetes complications, circulatory diseases (arteriosclerosis, hypertension, etc.) or obesity caused by insulin resistance syndrome.
In addition, the concepts of Syndrome X, metabolic syndrome, and the like have recently been advocated as disease states that increase the risk of coronary artery disease through a complex relationship with abnormal lipid metabolism diseases, diabetes, insulin resistance syndrome, and so forth (Reave, G. M., Diabetes, 1988, 37, 1595-1607; DeFronzo, R. A. et al., Diabetes Cara, 1991, 14, 173-194; Matsuzawa, Y., Nihon-Naikagaku-Zasshi (J. Jap. Soc. Internal Medicine), 1995, 84, 209-212). As previously described, since adiponectin is able to contribute to the treatment or prevention of the respective causes of Syndrome X, metabolic syndrome, and the like a medicament that enhances the production of adiponectin is also useful for the treatment or prevention of Syndrome X, metabolic syndrome, and the like.
On the basis of the above, a medicament that enhances adiponectin production has an action of improving insulin resistance and is useful as a pharmaceutical composition for enhancement of adiponectin production; treatment or prevention of hypoadiponectinemia; improvement of insulin resistance; treatment or prevention of Syndrome X or metabolic syndrome; treatment or prevention of diabetes, diabetes complications (including retinopathy, nephropathy, neuropathy, cataract, and coronary artery disease), hypertension, obesity or arteriosclerosis; or treatment or prevention of diabetes, diabetes complications (including retinopathy, nephropathy, neuropathy, cataract and coronary artery disease), hypertension, obesity or arteriosclerosis caused by hypoadiponectinemia or insulin resistance syndrome.
Although certain types of thiazolidine dione compounds or cannabinoid CB1 receptor antagonists are known to demonstrate action of enhancing adiponectin production (for example, Maeda, N. et al., Diabetes, 2001, 50, 2094-2099; Bensaid, M. et al., Molecular Pharmacology, 2002, 360, 1623-1630; etc.), HMG-CoA reductase inhibitors have not been known to demonstrate adiponectin production enhancing action or therapeutic or preventive effects for hypoadiponectinemia.
HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitors are well-known hyperlipemia therapeutic medicaments (for example, U.S. Pat. No. 4,346,227, etc.). Statins are typical HMG-CoA reductase inhibitors, and disease preventive effects in humans have been confirmed in various clinical studies. For example, pravastatin has been reported to demonstrate effects (preventive effects) of suppressing the onset of arteriosclerosis, coronary artery disease and diabetes in a clinical study targeted at hyperlipemia patients (for example, MacMahon, S. et al., Circulation, 1998, 97, 1784-1790; Shepherd, J. et al., Lancet, 2002, 360, 1623-1630; Freeman, D. J. et al., Circulation, 2001, 103, 357-362; etc.).
However, HMG-CoA reductase inhibitors are not known to demonstrate therapeutic effects for arteriosclerosis or diabetes, or therapeutic or preventive effects for diabetes complications, hypertension or obesity.
In addition, although certain types of HMG-CoA reductase inhibitors have been reported to have an action of improving insulin resistance (for example, Mangaloglu, L. et al., Metabolism, Clinical and Experimental, 2002, 51, 409-418; Cingozbay, B. Y. et al., Journal of International Medical Research, 2002, 30, 21-25; Paolisso, G. et al., Atherosclerosis, 2000, 150, 121-127; etc.), pravastatin and rosuvastatin have heretofore not been known to have an action of improving insulin resistance.